Midazolam, i.e. 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]diazepine of the formula: is a well-documented product with sedative, anxiolytic, amnesic and hypnotic properties. It is commercially available in the form of its hydrochloride, for example in the form of a glycerin-based syrup sold under the trade mark VERSED® which contains 2.5 mg/mL of midazolam. It is also sold in the form of its maleate salt, for example in tablets containing 7.5 mg or 15 mg per tablet of midazolam under the trade mark DORMICUM®. The maleate salt contains 1:1 midazolam:maleic acid on a molar basis and hence is an acid salt.
It is known that midazolam can exist in solution both in a closed ring form and also in an open ring form which are in equilibrium with one another: 
The amount of the open ring form (Ia) present in aqueous solution depends upon the pH of the solution. In a typical syrup for oral administration, i.e. VERSED® syrup, the pH is typically approximately 3 and the proportion of the open ring form (Ia) may be about 40%. However, at physiological pHs of about 7.4, any open ring form present is reported to revert to the physiological, lipophilic closed ring form (I) and is absorbed as such.
Epileptic seizures (convulsive status epilepticus) are a common cause of neurological medical emergency and often result in brain damage. Failure to relieve the symptoms of an epileptic seizure in less than about 15 minutes can lead to death. Accordingly it is extremely desirable to treat very promptly a patient with an epileptic seizure and to relieve the corresponding symptoms as quickly as possible so as to minimise the risk of brain damage or death for the patient.
A comparison between intranasal and intravenous administration of midazolam for treating epileptic seizures in children has been described by E. Lahat et al., BMJ 2000: 321: pages 83 to 86 (8Jul. 2000). A dosage of 0.2 mg/kg intranasal midazolam is recommended with the corresponding recommended intravenous dose corresponding to 0.3 mg/kg. A solution containing 5 mg/mL of midazolam was used for intranasal administration. Control of seizures in used for intranasal administration. Control of seizures in children was reported to be faster by the intravenous route but the time to cessation of seizures was faster using the intranasal route.
Buccal administration of midazolam to treat seizures in students suffering from epilepsy has been reported by R. C. Scott et al., The Lancet, 353, Feb. 20, 1999, pages 623 to 626. These studies were conducted using a solution containing midazolam hydrochloride. The dosage used was 2 mL (10 mg) which was drawn into a 2 mL syringe. For administration the patient's lips were parted and the contents of the syringe squirted around buccal mucosa. However, even when the amount of liquid to be administered is no more than 2 mL, there may be difficulty in actually administering this quantity to a patient suffering an epileptic seizure whose jaws are clamped tightly shut as a result of the seizure.
Another well known use of midazolam is as an anaesthetic. Typically midazolam is administered intramuscularly when used as an anaesthetic. However, in emergency situations, such as at the scene of a car crash, particularly when the patient is wearing bulky clothing and has suffered bone fracture, the use of the intramuscular route may not be desirable.
There is accordingly a need to provide an improved form of medicament for the treatment of patients suffering epileptic seizure. There is a further need to provide a novel form of liquid pharmaceutical composition which enables an effective dose of midazolam (e.g. about 10 mg) to be administered quickly and without difficulty to a patient suffering from an epileptic seizure. It would further be desirable to provide a form of medicament for administration via the buccal route in which a higher proportion of midazolam is present in the closed ring form (I) so as to be more readily fat-soluble and thus better able to cross the blood-brain barrier faster than forms of midazolam which contain a high proportion of the open ring form (Ia). In addition there is a need to provide a liquid medicament suitable for buccal administration as an effective anaesthetic for use in accident and other emergency situations to relieve pain until the patient can be transferred to hospital.